Hepatic sinusoidal obstruction syndrome and short-term application of 6-thioguanine in pediatric acute lymphoblastic leukemia

Abstract

Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMT genotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG (P < 0.0001). Eight of the 13 patients were heterozygous for low-activity TPMT variants, resulting in a 22.4-fold (95% confidence interval 7.1-70.7; P ≤ 0.0001) increased risk of hepatic SOS for heterozygotes in comparison to TPMT wild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMT genotypes.

Fig. 1. Treatment outline of AIEOP-BFM ALL 2000.

Details of treatment elements are listed in Supplementary Table 1. Results of the randomizations (R) and data on allogeneic hematopoietic stem cell transplantation (HSCT) have been published before [16, 27]. SR indicates standard risk; MR, intermediate risk; HR, high risk; closed boxes indicate treatment elements: I_A, Protocol I phase A; D⁺ indicates induction with dexamethasone and P+ with prednisone; I_B, Protocol I phase B; M, Protocol M; II, Protocol II; III, Protocol III; HR1′, HR2′ and HR3′ are intensive high-risk treatment blocks; 6-MP/MTX, interim maintenance or maintenance therapy with 6-mercaptopurine and methotrexate; CR cranial irradiation; closed red boxes indicate the treatment elements in which hepatic SOS cases were observed. The asterisk indicates the second episode of hepatic SOS in patient 16 (Table 2) (color figure online).